CA2055602A1 - Benzocycloalkenecarboxylic acid and process for it's preparation - Google Patents
Benzocycloalkenecarboxylic acid and process for it's preparationInfo
- Publication number
- CA2055602A1 CA2055602A1 CA002055602A CA2055602A CA2055602A1 CA 2055602 A1 CA2055602 A1 CA 2055602A1 CA 002055602 A CA002055602 A CA 002055602A CA 2055602 A CA2055602 A CA 2055602A CA 2055602 A1 CA2055602 A1 CA 2055602A1
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- Prior art keywords
- approximately
- hydroxy
- bromobenzoyl
- benzocyclobutene
- carboxylic acid
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/38—Unsaturated compounds containing keto groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
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- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
4-18007/=
Novel benzocycloalkenecarboxylic acid and process for its preparation Abstract The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic i.e.
the compound of the formula
Novel benzocycloalkenecarboxylic acid and process for its preparation Abstract The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic i.e.
the compound of the formula
Description
205~602 4- 1 8007/=
Novel benzocycloalkenecarboxYlic acid and process for its preparation The invention relates to the novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1 -carboxylic acid, i.e. the compound of the formula H~ ~COOH
,~ Br (I), ~ ' ~ '.
in free form or in salt forrn, to the use of this compound, to a process for the preparation of this compound and to pharmaceutical preparations containing the compound I in free form or in the form of a pharmaceutically acceptable salt.
The compound I can be in the form of a salt, in particular a pharmaceutically acceptable salt. Corresponding salts are salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts, for exatnple sodium or potassium salts, or such as alkaline earth metal salts, for example calcium or magnesium salts, or salts with ammonia, with an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine or an aliphatic amine which, if desired, is C-hydroxylated, for example a mono-, di- or tri-lower aLkylamine, such as methyl-, ethyl- or diethylamine, a mono-, di- or tri-hydroxy-lower alkylamine, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, an N-(hydroxy-loweralkyl)-N,N-di-lower alkylamine, such as 2-(dimethylamino)ethanol, or an N-(polyhydroxy-lower alkyl)-N-lower alkylamine, such as D-glucamine, or with a quaternary ammonium base, such as a quaternary aliphatic ammonium hydroxide, forexample tetrabutylammonium hydroxide. Salts which are not suitable for pharmaceutical uses and which are employed, for example, for the isolation or purification, respectively, of the compound I, in free form or in the form of a pharmaceudcally acceptable salt, are . , . . :
, . ~ :
, also included.
The rac:emic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, i.e. the 1:1 enantiomer mixture of (R)- and (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo-butene-1-carboxylic acid is known and is proposed, for example in the European Patent Application No. 0 132 566, as an antinociceptive and antiinflammatory pharrnaceutical active ingredient having prostaglandin synthesis-inhibiting properties. The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, in free form or in the form of a pharrnaceutically acceptable salt, also has valuable pharrnacological properties, for example antinociceptive, antiinflammatory and prostaglandin synthesis-inhibiting activides, to an extent which is comparable to the extent of the activities of the known racemate. Thus, for example, (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid has corresponding desired effects in the writhing test model (induction by phenyl-p-benzoquinone) on the mouse [in accordance with J.
Pharrnacol. exp. Therap. 125, 237 (1959)], where the ED50 is 5 mg/kg p.o., and also in the adjuvant arthritis test on the rat, in which an ED40 of 0.5 mglkg p.o. is found. Additionally, compared with the known racemate, the (S)-enandomer provided according to the invention has, however, surprising therapeutic advantages. In particular, the (S)-enantiomer is accumulated in the fatty tissue to a smaller extent. Thus, comparison experiments with 14C-labelled (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and 14C-labelled racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid on the rat show that on daily administration of in each case S mg/kg p.o. over a period of 10 days, radioactive material is incorporated into the fatty tissue on administration of the (S)-enantiomer in a lower concentration than on administratdon of the racemate. In pardcular with respect to a chronic administration of the acdve ingredient, this is to be valued as a considerable therapeutic advantage of the (S)-enandomer over the .racemate.
The compound I, in free form or in the form of a pharmaceutically acceptable salt, can accordingly be used, for examplej as acdve ingredient in antinociceptive, antiinflammatory and prostaglandin synthesis-inhibidng pharrnaceutical compositions, which are used, for example, for the treatment of inflammadons, such as inflammatory diseases of the rheumatic type, for example chronic arthrids. The invendon thus relates to the use of the compound I, in free form or in the form of a pharmaceutically acceptable salt, for the preparation of correspon~ing medicaments and for the therapeutic treatment of inflarnmadons, such as inflammatory diseases of the rheumadc type, for example chronic :~
arthritis. The preparation of the medicaments also includes the commercial preparation of the active substances.
In the ],uropean Patent Application No. 0132 566, it is stated that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid can be separated into the enantiomers by known methods, for example by reaction "with an optically active base that forms salts with the racemic acid and separation of the salts obtained in this manner, for example on the basis of their differing solubilities, into the diastereomers, from which the antipodes" can "be set free by the action of suitable agents". However, more detailed information about the nature of the optically active base to be used is lacking in the European Patent Application No. 0 132 566. If, for example, quinine is used as the optically active base and customary methods of fractional crystallisation are carried out, only moderate yields of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- -1-carboxylic acid are obtained (see Comparison Example 1). The yield of the desired (S)-enantiomer cannot be improved even by increasing the number of crystallisation steps (see Comparison Example 2).
It has now surprisingly been found that (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo-butene-1-carboxylic acid of high to complete, for example at least 85 %, i.e. 85 % to 100 %, such as approximately 90 % to approximately 99 %, for example at least 92 %, optical purity is obtained in yields of over 90 % of theory if racemic 4-(2-bromobenzoyl)-S-hydroxy-benzocyclobutene-1-carboxylic acid is reacted at elevated temperature with at least the equimolar amount of quinine in an alcoholic solvent for from approximately 6 to approximately 48 hours, the quinine salt of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, pNcipitated in crystalline form as the direct reaction product, is separated from the reaction mixture, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free from this salt by acid treatment in a customaIy manner.
The invention therefore furthermore relates to a novel process for the preparation of the compound I, in free forrn or in salt form, characterised in that racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted at elevated temperature with at least the equimolar amount of quinine in an alcoholic solvent for from approximately 6 to approximately 48 hours, the quinine salt of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, is separated from the reaction mixture, and .
20556~)2 the (5)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free from this salt by acid treatment in a customary manner, and, if desired, this free acid is converted into a salt.
Suitable alcoholic solvents are in particular lower alkanols, i.e. Cl-C7alkanols, such as Cl-C4alkanols, for example methanol, ethanol, propanol, isopropanol or butanol, in particular ethanol. The amount of the alcoholic solvent is not criticial; however, at least the amount of alcohol necessary for complete dissolution of the components is required.
For example, approximately 8 to approximately 50 ml, preferably approximately 20 to approximately 30 ml, of the alcoholic solvent are estimated per g of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid.
The reaction time amounts to from approximately 6 to approximately 48 hours, in most cases advantageously from approximately 12 to approximately 24 hours.
The reaction temperature is not critical, provided that it is significantly elevaeed compared with the room temperature. The reaction is advantageously carried out, for example, in a temperature range of from approximately 50 to approximately 120C, in particular between approximately 60 and approximately 90C, preferably at the boiling temperature of the alcoholic solvent used.
The amount of quinine is not critical, provided that at least the equimolar amount of quinine is employed. For example, 1.0 time to approximately 1.5 times, preferably approximately 1.05 times to approximately 1.3 times, in particular approximately 1.15 times to approximately 1.25 times, the molar amount of quinine proves favourable.
The separa~ion of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzo-cyclobutene-1-carboxylic acid, precipitated accordirlg to the process in crystalline form as the direct reaction product, from the reaction mixture is carried out in a customary manner, for example by filtration, suction filtration or centrifugation.
The liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, by acid treatment of its quinine salt obtained according to the process, is ca~ied out in a customary manner, for example by treatment with a mineral acid, such as a hydrohalic acid, for example hydrochloric acid. In this process, at least the equimolar amount, i.e. at least once, for example appr~ximately twice to approximately 10 times, in particular : . . . .
approximately twice to approximately 5 times, the molar amount of acid is used and the reaction is advantageously carried out in a two-phase system, formed from water and a water-immiscible or only partially water-miscible organic solvent, such as an aliphatic alcohol, such as a C4-C7alkanol, for example butanol, isobutanol, sec-butanol, tert-butanol or a pentanol, hexanol or heptanol, a lower fatty acid ester, such as a C2-C7alkanoic acid-CI-C4alkyl ester, for example ethyl acetate, an aromatic or araliphatic hydrocarbon, for example benzene or an alkyl derivative thereof, such as toluene or xylene, ahalogenated aliphatic hydrocarbon, such as a halo-C1-C4alkane, for example di- or trichloromethane, or an aliphatic ether, such as a di-CI-C4alkyl ether, for example tert-butyl methyl ether.
In a preferred embodiment of the process according to the invention, a solution of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and 1.0 time to approximately 1.5 times the molar amount, i.e. 0.94 to approximately 1.41 kg per kg of acid, of quinine in approximately 8 times to approximately 50 times the amount by volume, i.e. approximately 8 to approximately 501 per kg of acid, of a Cl-C4alkanol is heated to from approximately 60 ~o approximately 90C for from approximately 6 to approximately 48 hours, the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline forrn as the direct reaction product, is separated from the reaction mixture in a customary manner, and the (s)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free by acid treatment in a customary manner of its quinine salt obtained according to the process.
In a particularly preferred embodiment of the process according to the invention, a solution of racemic 4-(2-bromoben70yl)-5-hydroxy-benzocyclobutene-1-carbaxylic acid and approximately 1.05 dmes to approximately 1.3 times the molar amount, i.e.
approximately 0.99 to approximately 1.22 kg per kg of acid, of quinine in approximately 20 times to approximately 30 times the amount by volume, i.e. approximately 20 to approximately 301 per kg of acid, of ethanol is heated to the boiling temperature of the ethanol for from approximately 12 to approximately 24 hours, the quinine salt of(S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direction reaction product, is separated from the reaction mixture in a customary manner, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-I-carboxylic acid is set free by treatment of its quinine salt obtained according to the process with approximately twice to approximately 5 times the molar amount of hydrochloric acid in a two-phase system formed from water and tert-butyl methyl ether.
.
, : - :.
'', ', ' ~
.,, ~ .
The free (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid obtainable according to the process can be converted into one of its salts in a manner known per se, for example by reaction of a solution of the free acid in a suitable solvent or solvent mixture with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogencarbonate, ammonia or another of the salt-forming bases mentioned heréinbefore, or with a suitable ion exchange reagent.
The compound I can be obtained in free form or in salt form, depending on the procedure and the reaction conditions. As a result of the close relationship between the compound I
in the free from and in the form of its salts, the free compound I or its salts above and below is also to be understood as meaning accordingly and appropriately, where relevant, the corresponding salts or the free compound I.
The compound I, including its salts, can also be obtained in the form of hydrates and/or can include other solvents, for example those used for crystallisation.
The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as the starting substance and the missing steps are carried out.
The inverition likewise relates to novel intermediates for the preparation of the compound I, to their use and to a process for the* preparation.
The compound I and its pharmaceutically acceptable salts can be used, preferably in the forrn of pharmaceudcally acceptable formulations, in a method for the prophylacdc andlor therapeutic treatment of the animal or human body, in particular as andnocicepdve, antlinflammatory and prostaglandin synthesis-inhibidng pharmaceudcal composidons.
The invention thus likewise relates to pharmaceudcal preparadons containing the compound I as the active ingredient in the free form or in the form of a pharmaceudcally acceptable salt, and to a process for their preparadon. These pharmaceudcal preparations are those for enteral, such as oral and furthermore rectal, or parenteral administration to warrn-blooded animals, the preparation containing the pharmacological active ingredient by itself ~r together with customary pharmaceutical auxiliaries. The pharmaceudcal preparadons contain, for example, from about 0.1 % to 100 %, preferably from about 1 %
.. . .
.
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.; ............. ~ - . - : .
to about 50 %, of the active ingredient. Pharrnaceutical preparations for enteral or parenteral administration are, for examplet those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore arnpoules. These are prepared in a manner which is known per se, for exarnple by means of conventional mixing,granulating, sugar-coating, dissolving or Iyophilising processes. Pharrnaceutical preparations which are suitable for oral administration can thus be obtained by combining the active ingredient with solid carriers, if appropriate granulating the resulting mixture, and processing the mixture or granules, if desired or necessary after addition of suitable excipients, to give tablets or sugar-coated tablet cores.
Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the abovementioned starches, and also carboxymethyl starch, crosslinlcedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as socium alginate.
Excipients are chiefly glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
Sugar-coated tablet cores are provided with suitable coatings which can be resistant to gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol andlor titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or sugar coatings, for example to identify or indicate different doses of active ingredient.
Further pharmaceutical preparations capable of oral administration are dry-filled capsules of gelatin and also soft, sealed capsules made from gelatin and a plasdciser, such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as ta1c or magnesium stearate, and if appropriate stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilis~rs can also be added.
'"' ' .
Suitable pharmaceutical preparations for rectal adrninistration are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base. ~;xamples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher aL~canols. Gelatin rectal capsules, which contain a combination of the active ingredient with a base material, can furthermore also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.
Suitable forms for parenteral administration are, in particular, aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as corresponding oily injection suspensions, in which case suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate also stabilisers.
The dosage of the active ingredient can depend on various factors, such as the mode of administration, the warm-blooded species, the age and/or condition of the individual. In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated for oral administration to a patient weighing about 75 kg.
The following examples illustrate the invention described above; however, they are not intended to limit this in its scope in any way. Temperatures are stated in degrees Celsius.
Exemplary embodiment: a) 3.47 g (10 mmol) of racernic 4-(2-bromobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are dissolved in 40 ml of absolute ethanol.
The mixture is heated to 70 and a solution of 3.89 g (12 mmol) of quinine in 40 ml of absolute ethanol is added. The temperature of the mixture decreases to 58. The reaction mixture is heated to reflux with stirring (internal temperature: 77). After about 30 minutes, the deposition of crystals begins on the vessel wall. The mixture is heated at reflux with stirring for a further 20.5 hours, allowed to cool to room temperature, and filtered with suction, and the filtration residue is washed twice with 5 ml of absolute ethanol each time and dried to constant weight. 6.31 g of the quinine salt of (S)-4-(2-bromoben~oy1)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [yield: 94.1 % of theory; (S):(R) ratio according to HPLC analysis: 2 96:4].
.:
b) A suspension of 61.5 g (91.7 mmol) of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid obtained according to step a) in 200 ml of tert-butyl methyl ether is treated at 0 with 100 ml of 2N hydrochloric acid while stirring.
The organic phase is separated off and the aqueous phase is extracted by shaking with 20 ml of tert-butyl methyl ether. The organic phases are combined, washed with water until neutral, dried over sodium sulfate and evaporated to dryness under reduced pressure. The resldue consists of 35.2 g of a highly viscous yellowish oil, which still contains some solvent and is crystallised from hexane. 31.4 g of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 104 to 105; [o~] D : -24.8 (1 % in CHCl3); (S):(R) ratio according to HPLC
analysis: 2 96.4]. The total yield over both steps is 93.1 % of theory.
Compa7ison Exarnple 1: 17.35 g (50.1 mmol) of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- l-carboxylic acid are suspended in 250 ml of absolute ethanol. The suspension is warmed to 40, 8.5 g (26.2 mmol) of quinine are added, and the mixture is heated to reflux. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid already begins to precipitate at a temperature of from 60 to 65C. The reaction mixture is stirred under reflux for S minutes and then allowed to cool to room temperature in the course of 1 hour, the white suspension is filtered with suction, and the filter cake is washed twice with 30 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid is thus obtained (crystallisation step 1). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 100 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated underreduced pressure. The 4-(2-bromobenzoyl)-5-hydroxy-benzocyclo- butene-1-carboxylic acid thus obtained (crystallisation step 1) is dissolved in 100 ml of absolute ethanol, the solution is treated with 8.1 g (25 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes~ The reaction mixture is allowed to cool to room temperature in the course of 1 hour and is filtered vith suction, the filter cake is washed twice with 20 ml of absolute ethanol each time and sucked dry. The quinine salt of (S)-4-(2-bromobenzoyl)-S-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 2). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 100 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
The crude (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo- butene-1-carboxylic acid thus obtained (crystallisation step 2) is dissolved in diethyl ether, and the solution is treated with petroleum ether until the onset of turbidity. The mixture is stirred for some time and filtered with suction, and the ~llter cake is dried overnight under reduced pressure at 40.
4.7 g of pure (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 103 to 104; [~]D : -24.1 + 1.1; (S):(R) ratio according to HPLC
analysis: 2 99:1; total yield: 27.1 % of theory].
Comparison Example 2: 34.7 g (100 mmol) of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are dissolved in 800 ml of absolute ethanol. The solution is warmed to 40, 32.4 g (100 mmol) of quinine are added, and the reaction mixture is heated to reflux. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid already begins to precipitate at a temperature of 70.
The reaction mixture is stirred under reflux for 5 minutes and then allowed to cool to 35 in the course of 1 hour, the white suspension is filtered with suction, and the filter cake is washed twice with 100 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 1). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 200 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure. 24 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained (crystallisation step 1). This acid is dissolved in 800 ml of ethanol, the solution is treated with 22.4 g (69 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is filtered with suction, and the filter cake is washed twice with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained(crystallisation step 2). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 135 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
17 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thusobtained (crystallisation st~p 2). This acid is dissolved in 800 ml of absolute ethanol, the solution is treated with 15.9 g (49 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is filtered with suction, and the filter cake is washed twice . ~ . .
- :
, - 1 1 - 20S56(~2 with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained(crystallisation step 3). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 98 ml of 2N hydrochloric acid, washed twice with 40 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
14 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thusobtained (crystallisation step 3). This acid is dissolved in 800 ml of absolute ethanol, the solution is treated with 13.1 g (40 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is ~lltered with suction, and the filter cake is washed twice with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 4). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 81 ml of 2N hydrochloric acid, washed twice with 40 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
10.5 g of crude (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained (crystallisation step 4). This acid is dissolved in diethyl ether and the solution is treated with petroleum ether until the onset of turbidity. The mixturc is stirred for some time and filtered with suction, and the filter cake is dried overnight under reduced pressure at 40. 8.8 g of pure (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 103 to 104; [~1 D : -26.1 + 1.0; (S):(R) ratio according to HPLC analysis: 2 99.5:0.5; total yield: 25.4 % of theory].
Preparation ExarnPle 1: Tablets, each containing as active ingredient 50 mg of (S3-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a salt thereof, for example the sodium salt, can be prepared as follows:
Composition (for 10~000 tablets):
Active ingredient 500.0 g Lactose 500.0 g Pota~o starch 352.0 g Geladn 8.0 g Talc 60.0 g Magnesium stearate 10.0 g Silica (highly disperse) 20.0 g Ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica are admixed and the mixture is compressed to give tablets each of weight 145 mg and active ingredient content 50 mg, which, if desired, can be provided with breaking notches for finer adjustment of the dosage.
Preparation Example 2: Film-coated tablets, each containing as active ingredient 100 mg of ~S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a saltthereof, for example the sodium salt, can be prepared as follows:
Composition (for 1000 film-coated tablets):
Active ingredient 100.0 g Lactose 100.0 g Maize starch 70.0 g Talc 8.5 g Calcium stearate 1.5 g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s.
Dichloromethane q.s.
The active ingredient, the lactose and 40 g of the maize starch are mixed. The mixture is moistened with a paste prepared from- 15 g of maize starch and water (with warming), and is granulated. The granules are dried, and the remainder of the maize starch, the talc and the calcium stearate are mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg each) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the film-coated tablets: 283 mg each).
Preparation ExamPle 3: Hard gelatin capsules, each containing as active ingredient 100 g of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a saltthereof, for example the sodium salt, can be prepared as follows:
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Composition (for 1000 capsules):
Active ingredient 100.0 g Lactose 250.0 g Microcrystalline cellulose 30.0 g Sodium lauryl sulfate 2.0 g Magnesium stearate 8.0 g The sodium lauryl sulfate is sieved into the lyophilised active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. The lactose is then first sieved in through a sieve having a mesh width of 0.6 mm and subsequently the microcrystalline cellulose through a sieve having a mesh width of 0.9 mm. A11 four components are then intimately mixed for 10 minutes. Finally, the magnesium stearate is sieved in through a sieve having a mesh width of 0.8 mm. After further mixing (3minutes), 390 mg each of the formulation obtained is filled into hard gelatin capsules of size 0.
Preparation Example 4: An injection or infusion soludon, containing as acdve ingredient (S)-4-~2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a salt thereof, for example the sodium salt, can be prepared as follows:
Com~osition (for 1000 ampoules):
Active ingredient 5.0 g Sodium chloride 22.5 g Phosphate buffer solution (pH: 7.4) 300.0 g Demineralised water to 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of demineralised water. The soludon is filtered through a microfilter. The filtrate is treated with the phosphate buffer solution, and the mixture is made up to 2500 ml with demineralised water. To prepare unit dose forms, 2.5 ml of the mixture each time are filled into glass ampoules, which then each contain 5 mg of active ingredient.
Novel benzocycloalkenecarboxYlic acid and process for its preparation The invention relates to the novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1 -carboxylic acid, i.e. the compound of the formula H~ ~COOH
,~ Br (I), ~ ' ~ '.
in free form or in salt forrn, to the use of this compound, to a process for the preparation of this compound and to pharmaceutical preparations containing the compound I in free form or in the form of a pharmaceutically acceptable salt.
The compound I can be in the form of a salt, in particular a pharmaceutically acceptable salt. Corresponding salts are salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts, for exatnple sodium or potassium salts, or such as alkaline earth metal salts, for example calcium or magnesium salts, or salts with ammonia, with an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine or an aliphatic amine which, if desired, is C-hydroxylated, for example a mono-, di- or tri-lower aLkylamine, such as methyl-, ethyl- or diethylamine, a mono-, di- or tri-hydroxy-lower alkylamine, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, an N-(hydroxy-loweralkyl)-N,N-di-lower alkylamine, such as 2-(dimethylamino)ethanol, or an N-(polyhydroxy-lower alkyl)-N-lower alkylamine, such as D-glucamine, or with a quaternary ammonium base, such as a quaternary aliphatic ammonium hydroxide, forexample tetrabutylammonium hydroxide. Salts which are not suitable for pharmaceutical uses and which are employed, for example, for the isolation or purification, respectively, of the compound I, in free form or in the form of a pharmaceudcally acceptable salt, are . , . . :
, . ~ :
, also included.
The rac:emic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, i.e. the 1:1 enantiomer mixture of (R)- and (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo-butene-1-carboxylic acid is known and is proposed, for example in the European Patent Application No. 0 132 566, as an antinociceptive and antiinflammatory pharrnaceutical active ingredient having prostaglandin synthesis-inhibiting properties. The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, in free form or in the form of a pharrnaceutically acceptable salt, also has valuable pharrnacological properties, for example antinociceptive, antiinflammatory and prostaglandin synthesis-inhibiting activides, to an extent which is comparable to the extent of the activities of the known racemate. Thus, for example, (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid has corresponding desired effects in the writhing test model (induction by phenyl-p-benzoquinone) on the mouse [in accordance with J.
Pharrnacol. exp. Therap. 125, 237 (1959)], where the ED50 is 5 mg/kg p.o., and also in the adjuvant arthritis test on the rat, in which an ED40 of 0.5 mglkg p.o. is found. Additionally, compared with the known racemate, the (S)-enandomer provided according to the invention has, however, surprising therapeutic advantages. In particular, the (S)-enantiomer is accumulated in the fatty tissue to a smaller extent. Thus, comparison experiments with 14C-labelled (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and 14C-labelled racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid on the rat show that on daily administration of in each case S mg/kg p.o. over a period of 10 days, radioactive material is incorporated into the fatty tissue on administration of the (S)-enantiomer in a lower concentration than on administratdon of the racemate. In pardcular with respect to a chronic administration of the acdve ingredient, this is to be valued as a considerable therapeutic advantage of the (S)-enandomer over the .racemate.
The compound I, in free form or in the form of a pharmaceutically acceptable salt, can accordingly be used, for examplej as acdve ingredient in antinociceptive, antiinflammatory and prostaglandin synthesis-inhibidng pharrnaceutical compositions, which are used, for example, for the treatment of inflammadons, such as inflammatory diseases of the rheumatic type, for example chronic arthrids. The invendon thus relates to the use of the compound I, in free form or in the form of a pharmaceutically acceptable salt, for the preparation of correspon~ing medicaments and for the therapeutic treatment of inflarnmadons, such as inflammatory diseases of the rheumadc type, for example chronic :~
arthritis. The preparation of the medicaments also includes the commercial preparation of the active substances.
In the ],uropean Patent Application No. 0132 566, it is stated that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid can be separated into the enantiomers by known methods, for example by reaction "with an optically active base that forms salts with the racemic acid and separation of the salts obtained in this manner, for example on the basis of their differing solubilities, into the diastereomers, from which the antipodes" can "be set free by the action of suitable agents". However, more detailed information about the nature of the optically active base to be used is lacking in the European Patent Application No. 0 132 566. If, for example, quinine is used as the optically active base and customary methods of fractional crystallisation are carried out, only moderate yields of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- -1-carboxylic acid are obtained (see Comparison Example 1). The yield of the desired (S)-enantiomer cannot be improved even by increasing the number of crystallisation steps (see Comparison Example 2).
It has now surprisingly been found that (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo-butene-1-carboxylic acid of high to complete, for example at least 85 %, i.e. 85 % to 100 %, such as approximately 90 % to approximately 99 %, for example at least 92 %, optical purity is obtained in yields of over 90 % of theory if racemic 4-(2-bromobenzoyl)-S-hydroxy-benzocyclobutene-1-carboxylic acid is reacted at elevated temperature with at least the equimolar amount of quinine in an alcoholic solvent for from approximately 6 to approximately 48 hours, the quinine salt of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, pNcipitated in crystalline form as the direct reaction product, is separated from the reaction mixture, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free from this salt by acid treatment in a customaIy manner.
The invention therefore furthermore relates to a novel process for the preparation of the compound I, in free forrn or in salt form, characterised in that racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted at elevated temperature with at least the equimolar amount of quinine in an alcoholic solvent for from approximately 6 to approximately 48 hours, the quinine salt of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, is separated from the reaction mixture, and .
20556~)2 the (5)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free from this salt by acid treatment in a customary manner, and, if desired, this free acid is converted into a salt.
Suitable alcoholic solvents are in particular lower alkanols, i.e. Cl-C7alkanols, such as Cl-C4alkanols, for example methanol, ethanol, propanol, isopropanol or butanol, in particular ethanol. The amount of the alcoholic solvent is not criticial; however, at least the amount of alcohol necessary for complete dissolution of the components is required.
For example, approximately 8 to approximately 50 ml, preferably approximately 20 to approximately 30 ml, of the alcoholic solvent are estimated per g of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid.
The reaction time amounts to from approximately 6 to approximately 48 hours, in most cases advantageously from approximately 12 to approximately 24 hours.
The reaction temperature is not critical, provided that it is significantly elevaeed compared with the room temperature. The reaction is advantageously carried out, for example, in a temperature range of from approximately 50 to approximately 120C, in particular between approximately 60 and approximately 90C, preferably at the boiling temperature of the alcoholic solvent used.
The amount of quinine is not critical, provided that at least the equimolar amount of quinine is employed. For example, 1.0 time to approximately 1.5 times, preferably approximately 1.05 times to approximately 1.3 times, in particular approximately 1.15 times to approximately 1.25 times, the molar amount of quinine proves favourable.
The separa~ion of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzo-cyclobutene-1-carboxylic acid, precipitated accordirlg to the process in crystalline form as the direct reaction product, from the reaction mixture is carried out in a customary manner, for example by filtration, suction filtration or centrifugation.
The liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, by acid treatment of its quinine salt obtained according to the process, is ca~ied out in a customary manner, for example by treatment with a mineral acid, such as a hydrohalic acid, for example hydrochloric acid. In this process, at least the equimolar amount, i.e. at least once, for example appr~ximately twice to approximately 10 times, in particular : . . . .
approximately twice to approximately 5 times, the molar amount of acid is used and the reaction is advantageously carried out in a two-phase system, formed from water and a water-immiscible or only partially water-miscible organic solvent, such as an aliphatic alcohol, such as a C4-C7alkanol, for example butanol, isobutanol, sec-butanol, tert-butanol or a pentanol, hexanol or heptanol, a lower fatty acid ester, such as a C2-C7alkanoic acid-CI-C4alkyl ester, for example ethyl acetate, an aromatic or araliphatic hydrocarbon, for example benzene or an alkyl derivative thereof, such as toluene or xylene, ahalogenated aliphatic hydrocarbon, such as a halo-C1-C4alkane, for example di- or trichloromethane, or an aliphatic ether, such as a di-CI-C4alkyl ether, for example tert-butyl methyl ether.
In a preferred embodiment of the process according to the invention, a solution of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and 1.0 time to approximately 1.5 times the molar amount, i.e. 0.94 to approximately 1.41 kg per kg of acid, of quinine in approximately 8 times to approximately 50 times the amount by volume, i.e. approximately 8 to approximately 501 per kg of acid, of a Cl-C4alkanol is heated to from approximately 60 ~o approximately 90C for from approximately 6 to approximately 48 hours, the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline forrn as the direct reaction product, is separated from the reaction mixture in a customary manner, and the (s)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free by acid treatment in a customary manner of its quinine salt obtained according to the process.
In a particularly preferred embodiment of the process according to the invention, a solution of racemic 4-(2-bromoben70yl)-5-hydroxy-benzocyclobutene-1-carbaxylic acid and approximately 1.05 dmes to approximately 1.3 times the molar amount, i.e.
approximately 0.99 to approximately 1.22 kg per kg of acid, of quinine in approximately 20 times to approximately 30 times the amount by volume, i.e. approximately 20 to approximately 301 per kg of acid, of ethanol is heated to the boiling temperature of the ethanol for from approximately 12 to approximately 24 hours, the quinine salt of(S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direction reaction product, is separated from the reaction mixture in a customary manner, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-I-carboxylic acid is set free by treatment of its quinine salt obtained according to the process with approximately twice to approximately 5 times the molar amount of hydrochloric acid in a two-phase system formed from water and tert-butyl methyl ether.
.
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The free (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid obtainable according to the process can be converted into one of its salts in a manner known per se, for example by reaction of a solution of the free acid in a suitable solvent or solvent mixture with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogencarbonate, ammonia or another of the salt-forming bases mentioned heréinbefore, or with a suitable ion exchange reagent.
The compound I can be obtained in free form or in salt form, depending on the procedure and the reaction conditions. As a result of the close relationship between the compound I
in the free from and in the form of its salts, the free compound I or its salts above and below is also to be understood as meaning accordingly and appropriately, where relevant, the corresponding salts or the free compound I.
The compound I, including its salts, can also be obtained in the form of hydrates and/or can include other solvents, for example those used for crystallisation.
The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as the starting substance and the missing steps are carried out.
The inverition likewise relates to novel intermediates for the preparation of the compound I, to their use and to a process for the* preparation.
The compound I and its pharmaceutically acceptable salts can be used, preferably in the forrn of pharmaceudcally acceptable formulations, in a method for the prophylacdc andlor therapeutic treatment of the animal or human body, in particular as andnocicepdve, antlinflammatory and prostaglandin synthesis-inhibidng pharmaceudcal composidons.
The invention thus likewise relates to pharmaceudcal preparadons containing the compound I as the active ingredient in the free form or in the form of a pharmaceudcally acceptable salt, and to a process for their preparadon. These pharmaceudcal preparations are those for enteral, such as oral and furthermore rectal, or parenteral administration to warrn-blooded animals, the preparation containing the pharmacological active ingredient by itself ~r together with customary pharmaceutical auxiliaries. The pharmaceudcal preparadons contain, for example, from about 0.1 % to 100 %, preferably from about 1 %
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to about 50 %, of the active ingredient. Pharrnaceutical preparations for enteral or parenteral administration are, for examplet those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore arnpoules. These are prepared in a manner which is known per se, for exarnple by means of conventional mixing,granulating, sugar-coating, dissolving or Iyophilising processes. Pharrnaceutical preparations which are suitable for oral administration can thus be obtained by combining the active ingredient with solid carriers, if appropriate granulating the resulting mixture, and processing the mixture or granules, if desired or necessary after addition of suitable excipients, to give tablets or sugar-coated tablet cores.
Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the abovementioned starches, and also carboxymethyl starch, crosslinlcedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as socium alginate.
Excipients are chiefly glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
Sugar-coated tablet cores are provided with suitable coatings which can be resistant to gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol andlor titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or sugar coatings, for example to identify or indicate different doses of active ingredient.
Further pharmaceutical preparations capable of oral administration are dry-filled capsules of gelatin and also soft, sealed capsules made from gelatin and a plasdciser, such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as ta1c or magnesium stearate, and if appropriate stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilis~rs can also be added.
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Suitable pharmaceutical preparations for rectal adrninistration are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base. ~;xamples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher aL~canols. Gelatin rectal capsules, which contain a combination of the active ingredient with a base material, can furthermore also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.
Suitable forms for parenteral administration are, in particular, aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as corresponding oily injection suspensions, in which case suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate also stabilisers.
The dosage of the active ingredient can depend on various factors, such as the mode of administration, the warm-blooded species, the age and/or condition of the individual. In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated for oral administration to a patient weighing about 75 kg.
The following examples illustrate the invention described above; however, they are not intended to limit this in its scope in any way. Temperatures are stated in degrees Celsius.
Exemplary embodiment: a) 3.47 g (10 mmol) of racernic 4-(2-bromobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid are dissolved in 40 ml of absolute ethanol.
The mixture is heated to 70 and a solution of 3.89 g (12 mmol) of quinine in 40 ml of absolute ethanol is added. The temperature of the mixture decreases to 58. The reaction mixture is heated to reflux with stirring (internal temperature: 77). After about 30 minutes, the deposition of crystals begins on the vessel wall. The mixture is heated at reflux with stirring for a further 20.5 hours, allowed to cool to room temperature, and filtered with suction, and the filtration residue is washed twice with 5 ml of absolute ethanol each time and dried to constant weight. 6.31 g of the quinine salt of (S)-4-(2-bromoben~oy1)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [yield: 94.1 % of theory; (S):(R) ratio according to HPLC analysis: 2 96:4].
.:
b) A suspension of 61.5 g (91.7 mmol) of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid obtained according to step a) in 200 ml of tert-butyl methyl ether is treated at 0 with 100 ml of 2N hydrochloric acid while stirring.
The organic phase is separated off and the aqueous phase is extracted by shaking with 20 ml of tert-butyl methyl ether. The organic phases are combined, washed with water until neutral, dried over sodium sulfate and evaporated to dryness under reduced pressure. The resldue consists of 35.2 g of a highly viscous yellowish oil, which still contains some solvent and is crystallised from hexane. 31.4 g of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 104 to 105; [o~] D : -24.8 (1 % in CHCl3); (S):(R) ratio according to HPLC
analysis: 2 96.4]. The total yield over both steps is 93.1 % of theory.
Compa7ison Exarnple 1: 17.35 g (50.1 mmol) of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- l-carboxylic acid are suspended in 250 ml of absolute ethanol. The suspension is warmed to 40, 8.5 g (26.2 mmol) of quinine are added, and the mixture is heated to reflux. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid already begins to precipitate at a temperature of from 60 to 65C. The reaction mixture is stirred under reflux for S minutes and then allowed to cool to room temperature in the course of 1 hour, the white suspension is filtered with suction, and the filter cake is washed twice with 30 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid is thus obtained (crystallisation step 1). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 100 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated underreduced pressure. The 4-(2-bromobenzoyl)-5-hydroxy-benzocyclo- butene-1-carboxylic acid thus obtained (crystallisation step 1) is dissolved in 100 ml of absolute ethanol, the solution is treated with 8.1 g (25 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes~ The reaction mixture is allowed to cool to room temperature in the course of 1 hour and is filtered vith suction, the filter cake is washed twice with 20 ml of absolute ethanol each time and sucked dry. The quinine salt of (S)-4-(2-bromobenzoyl)-S-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 2). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 100 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
The crude (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclo- butene-1-carboxylic acid thus obtained (crystallisation step 2) is dissolved in diethyl ether, and the solution is treated with petroleum ether until the onset of turbidity. The mixture is stirred for some time and filtered with suction, and the ~llter cake is dried overnight under reduced pressure at 40.
4.7 g of pure (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 103 to 104; [~]D : -24.1 + 1.1; (S):(R) ratio according to HPLC
analysis: 2 99:1; total yield: 27.1 % of theory].
Comparison Example 2: 34.7 g (100 mmol) of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are dissolved in 800 ml of absolute ethanol. The solution is warmed to 40, 32.4 g (100 mmol) of quinine are added, and the reaction mixture is heated to reflux. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene- 1-carboxylic acid already begins to precipitate at a temperature of 70.
The reaction mixture is stirred under reflux for 5 minutes and then allowed to cool to 35 in the course of 1 hour, the white suspension is filtered with suction, and the filter cake is washed twice with 100 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 1). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 200 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure. 24 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained (crystallisation step 1). This acid is dissolved in 800 ml of ethanol, the solution is treated with 22.4 g (69 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is filtered with suction, and the filter cake is washed twice with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained(crystallisation step 2). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 135 ml of 2N hydrochloric acid, washed twice with 50 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
17 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thusobtained (crystallisation st~p 2). This acid is dissolved in 800 ml of absolute ethanol, the solution is treated with 15.9 g (49 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is filtered with suction, and the filter cake is washed twice . ~ . .
- :
, - 1 1 - 20S56(~2 with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained(crystallisation step 3). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 98 ml of 2N hydrochloric acid, washed twice with 40 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
14 g of 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thusobtained (crystallisation step 3). This acid is dissolved in 800 ml of absolute ethanol, the solution is treated with 13.1 g (40 mmol) of quinine, and the reaction mixture is heated to reflux and stirred under reflux for S minutes. The reaction mixture is allowed to cool to 35 in the course of 1 hour and is ~lltered with suction, and the filter cake is washed twice with 60 ml of absolute ethanol each time and sucked dry. The quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is thus obtained (crystallisation step 4). This salt is dissolved in 200 ml of ethyl acetate, and the solution is extracted by shaking with 81 ml of 2N hydrochloric acid, washed twice with 40 ml of water each time, dried over magnesium sulfate and evaporated under reduced pressure.
10.5 g of crude (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained (crystallisation step 4). This acid is dissolved in diethyl ether and the solution is treated with petroleum ether until the onset of turbidity. The mixturc is stirred for some time and filtered with suction, and the filter cake is dried overnight under reduced pressure at 40. 8.8 g of pure (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid are thus obtained [m.p.: 103 to 104; [~1 D : -26.1 + 1.0; (S):(R) ratio according to HPLC analysis: 2 99.5:0.5; total yield: 25.4 % of theory].
Preparation ExarnPle 1: Tablets, each containing as active ingredient 50 mg of (S3-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a salt thereof, for example the sodium salt, can be prepared as follows:
Composition (for 10~000 tablets):
Active ingredient 500.0 g Lactose 500.0 g Pota~o starch 352.0 g Geladn 8.0 g Talc 60.0 g Magnesium stearate 10.0 g Silica (highly disperse) 20.0 g Ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica are admixed and the mixture is compressed to give tablets each of weight 145 mg and active ingredient content 50 mg, which, if desired, can be provided with breaking notches for finer adjustment of the dosage.
Preparation Example 2: Film-coated tablets, each containing as active ingredient 100 mg of ~S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a saltthereof, for example the sodium salt, can be prepared as follows:
Composition (for 1000 film-coated tablets):
Active ingredient 100.0 g Lactose 100.0 g Maize starch 70.0 g Talc 8.5 g Calcium stearate 1.5 g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s.
Dichloromethane q.s.
The active ingredient, the lactose and 40 g of the maize starch are mixed. The mixture is moistened with a paste prepared from- 15 g of maize starch and water (with warming), and is granulated. The granules are dried, and the remainder of the maize starch, the talc and the calcium stearate are mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg each) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the film-coated tablets: 283 mg each).
Preparation ExamPle 3: Hard gelatin capsules, each containing as active ingredient 100 g of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a saltthereof, for example the sodium salt, can be prepared as follows:
. ~ , ' ~. ;: ., ~' . .
- ::
Composition (for 1000 capsules):
Active ingredient 100.0 g Lactose 250.0 g Microcrystalline cellulose 30.0 g Sodium lauryl sulfate 2.0 g Magnesium stearate 8.0 g The sodium lauryl sulfate is sieved into the lyophilised active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed. The lactose is then first sieved in through a sieve having a mesh width of 0.6 mm and subsequently the microcrystalline cellulose through a sieve having a mesh width of 0.9 mm. A11 four components are then intimately mixed for 10 minutes. Finally, the magnesium stearate is sieved in through a sieve having a mesh width of 0.8 mm. After further mixing (3minutes), 390 mg each of the formulation obtained is filled into hard gelatin capsules of size 0.
Preparation Example 4: An injection or infusion soludon, containing as acdve ingredient (S)-4-~2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid or a salt thereof, for example the sodium salt, can be prepared as follows:
Com~osition (for 1000 ampoules):
Active ingredient 5.0 g Sodium chloride 22.5 g Phosphate buffer solution (pH: 7.4) 300.0 g Demineralised water to 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of demineralised water. The soludon is filtered through a microfilter. The filtrate is treated with the phosphate buffer solution, and the mixture is made up to 2500 ml with demineralised water. To prepare unit dose forms, 2.5 ml of the mixture each time are filled into glass ampoules, which then each contain 5 mg of active ingredient.
Claims (45)
1. A process for the preparation of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzo-cyclobutene-1-carboxylic acid, i.e. the compound of the formula (I), in free form or in salt form, characterised in that racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted at elevated temperature with at least the equimolar amount of quinine in an alcoholic solvent for from approximately 6 to approximately 48 hours, the quinine salt of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzo-cyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, is separated from the reaction mixture, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free from this salt by acid treatment in a customary manner, and, if desired, this free acid is converted into a salt.
2. A process according to claim 1, characterised in that a C1-C7alkanol is used as the alcoholic solvent.
3. A process according to claim 1 or 2, characterised in that a C1-C4alkanol is used as the alcoholic solvent.
4. A process according to any one of claims 1 to 3, characterised in that methanol, ethanol, propanol, isopropanol or butanol is used as the alcoholic solvent.
5. A process according to any one of claims 1 to 4, characterised in that ethanol is used as the alcoholic solvent.
6. A process according to any one of claims 1 to 5, characterised in that approximately 8 to approximately 50 ml of the alcoholic solvent are used per g of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid.
7. A process according to any one of claims 1 to 6, characterised in that approximately 20 to approximately 30 ml of the alcoholic solvent are used per g of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid.
8. A process according to any one of claims 1 to 7, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with quinine for from approximately 12 to approximately 24 hours.
9. A process according to any one of claims 1 to 8, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with quinine in a temperature range of from approximately 50° to approximately 120°C.
10. A process according to any one of claims 1 to 9, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with quinine in a temperature range of from approximately 60° to approximately 90°C.
11. A process according to any one of claims 1 to 10, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with quinine at the boiling temperature of the alcoholic solvent used.
12. A process according to any one of claims 1 to 11, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with 1.0 time to approximately 1.5 times the molar amount of quinine.
13. A process according to any one of claims 1 to 12, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with approximately 1.05 times to approximately 1.3 times the molar amount of quinine.
14. A process according to any one of claims 1 to 13, characterised in that the racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is reacted with approximately 1.15 times to approximately 1.25 times the molar amount of quinine.
15. A process according to any one of claims 1 to 14, characterised in that the separation of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, from the reaction mixture is carried out by filtration.
16. A process according to any one of claims 1 to 15, characterised in that the separation of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, from the reaction mixture is carried out by suction filtration.
17. A process according to any one of claims 1 to 14, characterised in that the separation of the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, from the reaction mixture is carried out by centrifugation.
18. A process according to any one of claims 1 to 17, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out by treatment with a mineral acid.
19. A process according to any one of claims 1 to 18, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out by treatment with a hydrohalic acid.
20. A process according to any one of claims 1 to 19, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out by treatment with hydrochloric acid.
21. A process according to any one of claims 1 to 20, characterised in that in the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from its quinine salt obtained according to the process the acid employed for the liberation is used at least in the equimolar amount.
22. A process according to any one of claims 1 to 21, characterised in that in the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from its quinine salt obtained according to the process the acid employed for the liberation is used at least in approximately twice to approximately 10 times the molar amount.
23. A process according to any one of claims 1 to 22, characterised in that in the liberation of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene1-carboxylic acid from its quinine salt obtained according to the process the acid employed for the liberation is used at least in approximately twice to approximately 5 times the molar amount.
24. A process according to any one of claims 1 to 23, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out in a two-phase system.
25. A process according to any one of claims 1 to 24, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out in a two-phase system, formed from water and a water-immiscible or only partially water-miscible organic solvent.
26. A process according to any one of claims 1 to 25, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out in a two-phase system, formed from water and an aliphatic alcohol, a lower fatty acid ester, an aromatic or araliphatic hydrocarbon, a halogenated aliphatic hydrocarbon or an aliphatic ether.
27. A process according to any one of claims 1 to 26, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out in a two-phase system, formed from water and a a [sic] C4-C7alkanol, a C2-C7alkanoic acid-C1-C4alkyl ester, benzene or an alkyl derivative thereof, a halo-C1-C4alkane or a di-C1-C4alkyl ether.
28. A process according to any one of claims 1 to 27, characterised in that the liberation of the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid from itsquinine salt obtained according to the process is carried out in a two-phase system, formed from water and tert-butyl methyl ether.
29. A process according to claim 1, characterised in that a solution of racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and 1.0 time to approximately l.5 times the molar amount, i.e. 0.94 to approximately 1.41 kg per kg of acid, of quinine in approximately 8 times to approximately 50 times the amount by volume, i.e. approximately 8 to approximately 50 1 per kg of acid, of a C1-C4alkanol is heated to from approximately 60° to approximately 90°C for from approximately 6 to approximately 48 hours, the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, is separated from the reaction mixture in a customary manner, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free by acid treatment in a customary manner of its quinine salt obtained according to the process.
30. A process according to claim 29, characterised in that a solution of racemic4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and approximately 1.05 times to approximately 1.3 times the molar amount, i.e. approximately 0.99 to approximately 1.22 kg per kg of acid, of quinine in approximately 20 times to approximately 30 times the amount by volume, i.e. approximately 20 to approximately 30 1 per kg of acid, of ethanol is heated to the boiling temperature of the ethanol for from approximately 12 to approximately 24 hours, the quinine salt of (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, precipitated in crystalline form as the direct reaction product, is separated from the reaction mixture in a customary manner, and the (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is set free by treatment of its quinine salt obtained according to the process with approximately twice to the approximately 5 times the molar amount of hydrochloric acid in a two-phase system formed from water and tert-butyl methyl ether.
31. (1S)-4-(2-Bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, in free form or in salt form, prepared by the process according to any one of claims 1 to 30 or by an obvious modification thereof.
32. The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, i.e. the compound of the formula (I), in free form or in salt form.
33. The compound according to claim 32, in free form or in the form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body.
34. A compound according to claim 32 or 33, in free form or in the form of a pharmaceutically acceptable salt, for use as an antinociceptive, antiinflammatory or prostaglandin synthesis-inhibiting pharmaceutical composition.
35. A pharmaceutical preparation containing, as the active ingredient, a compound according to any one of claims 32 to 34, in free form or in the form of a pharmaceutically acceptable salt, if appropriate in addition to customary pharmaceutical excipients.
36. An antinociceptive, antiinflammatory or prostaglandin synthesis-inhibiting pharmaceutical preparation according to claim 35, in which an antinociceptive, antiinflammatory or prostaglandin synthesis-inhibiting active ingredient is chosen.
37. A process for the preparation of a pharmaceutical preparation according to claim 35 or 36, to which the active ingredient is processed to give a pharmaceutical preparation, customary pharmaceutical excipients being mixed in if appropriate.
38. The process according to claim 37 for the preparation of an antinociceptive,antiinflammatory or prostaglandin synthesis-inhibiting pharmaceutical preparation according to claim 36, characterised in that an antinociceptive, antiiflammatory or prostaglandin synthesis-inhibiting active ingredient is chosen.
39. The use of a compound according to any one of claims 32 to 34, in free form or in the form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation.
40. The use of a compound according to any one of claims 32 to 34, in free form or in the form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation by a non-chemical route.
41. The use of a compound according to claim 39 or 40 for the preparation of an antinociceptive, antiinflammatory or prostaglandin synthesis inhibitor.
42. The use of a compound according to any one of claims 32 to 34, in free form or in the form of a pharmaceutically acceptable salt, or of a pharmaceutical preparation according to claim 35 or 36 for the treatment of inflammations, such as inflammatory diseases of the rheumatic type, for example chronic arthritis.
43. A method of treating inflammations, such as inflammatory diseases of the rheumatic type, for example chronic arthritis, which method comprises administering a compound according to any one of claims 32 to 34, in free form or in the form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 35 or 36.
44. The process of the exemplary embodiment.
45. The novel intermediates formed according to the process in the process according to any one of claims 1 to 30 and 44, and the novel end products obtainable.
FD 4.41 GR
FD 4.41 GR
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1010/90-4 | 1990-03-27 | ||
| CH101090 | 1990-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2055602A1 true CA2055602A1 (en) | 1991-09-28 |
Family
ID=4200343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002055602A Abandoned CA2055602A1 (en) | 1990-03-27 | 1991-03-19 | Benzocycloalkenecarboxylic acid and process for it's preparation |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5177257A (en) |
| EP (1) | EP0478721B1 (en) |
| JP (1) | JPH05500518A (en) |
| KR (1) | KR920701111A (en) |
| CN (1) | CN1055175A (en) |
| AR (1) | AR246948A1 (en) |
| AT (1) | ATE127444T1 (en) |
| AU (1) | AU643981B2 (en) |
| CA (1) | CA2055602A1 (en) |
| CS (1) | CS80891A2 (en) |
| DE (1) | DE59106417D1 (en) |
| ES (1) | ES2077219T3 (en) |
| FI (1) | FI915542A0 (en) |
| HU (1) | HUT60233A (en) |
| IE (1) | IE911003A1 (en) |
| IL (1) | IL97618A0 (en) |
| MX (1) | MX25042A (en) |
| MY (1) | MY104641A (en) |
| PL (1) | PL293021A1 (en) |
| PT (1) | PT97129A (en) |
| WO (1) | WO1991014671A1 (en) |
| YU (1) | YU53691A (en) |
| ZA (1) | ZA912262B (en) |
| ZW (1) | ZW3391A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR242947A1 (en) * | 1983-06-15 | 1993-06-30 | Ciba Geigy | Substituted benzophenones |
-
1991
- 1991-03-19 CA CA002055602A patent/CA2055602A1/en not_active Abandoned
- 1991-03-19 WO PCT/CH1991/000064 patent/WO1991014671A1/en active IP Right Grant
- 1991-03-19 JP JP3505146A patent/JPH05500518A/en active Pending
- 1991-03-19 DE DE59106417T patent/DE59106417D1/en not_active Expired - Fee Related
- 1991-03-19 KR KR1019910701678A patent/KR920701111A/en not_active Application Discontinuation
- 1991-03-19 US US07/776,385 patent/US5177257A/en not_active Expired - Fee Related
- 1991-03-19 AT AT91905069T patent/ATE127444T1/en not_active IP Right Cessation
- 1991-03-19 EP EP91905069A patent/EP0478721B1/en not_active Expired - Lifetime
- 1991-03-19 PL PL29302191A patent/PL293021A1/en unknown
- 1991-03-19 AU AU73459/91A patent/AU643981B2/en not_active Ceased
- 1991-03-19 ES ES91905069T patent/ES2077219T3/en not_active Expired - Lifetime
- 1991-03-19 HU HU914081A patent/HUT60233A/en unknown
- 1991-03-20 IL IL97618A patent/IL97618A0/en unknown
- 1991-03-25 PT PT97129A patent/PT97129A/en not_active Application Discontinuation
- 1991-03-25 MY MYPI91000492A patent/MY104641A/en unknown
- 1991-03-25 MX MX2504291A patent/MX25042A/en unknown
- 1991-03-26 ZA ZA912262A patent/ZA912262B/en unknown
- 1991-03-26 ZW ZW33/91A patent/ZW3391A1/en unknown
- 1991-03-26 CN CN91101858A patent/CN1055175A/en active Pending
- 1991-03-26 CS CS91808A patent/CS80891A2/en unknown
- 1991-03-26 YU YU53691A patent/YU53691A/en unknown
- 1991-03-26 AR AR91319321A patent/AR246948A1/en active
- 1991-03-26 IE IE100391A patent/IE911003A1/en unknown
- 1991-11-25 FI FI915542A patent/FI915542A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| HU914081D0 (en) | 1992-07-28 |
| DE59106417D1 (en) | 1995-10-12 |
| PL293021A1 (en) | 1992-12-28 |
| CS80891A2 (en) | 1991-11-12 |
| PT97129A (en) | 1991-11-29 |
| ATE127444T1 (en) | 1995-09-15 |
| JPH05500518A (en) | 1993-02-04 |
| AU7345991A (en) | 1991-10-21 |
| IL97618A0 (en) | 1992-06-21 |
| YU53691A (en) | 1994-04-05 |
| EP0478721A1 (en) | 1992-04-08 |
| AU643981B2 (en) | 1993-12-02 |
| IE911003A1 (en) | 1991-10-09 |
| CN1055175A (en) | 1991-10-09 |
| HUT60233A (en) | 1992-08-28 |
| WO1991014671A1 (en) | 1991-10-03 |
| ZA912262B (en) | 1991-11-27 |
| AR246948A1 (en) | 1994-10-31 |
| ES2077219T3 (en) | 1995-11-16 |
| KR920701111A (en) | 1992-08-11 |
| FI915542A0 (en) | 1991-11-25 |
| US5177257A (en) | 1993-01-05 |
| ZW3391A1 (en) | 1991-10-30 |
| EP0478721B1 (en) | 1995-09-06 |
| MX25042A (en) | 1993-12-01 |
| MY104641A (en) | 1994-04-30 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |